Review: autophagy in neurodegeneration: firefighter and/or incendiarist?

Abstract

Autophagy is an intracellular bulk degradation system that is found ubiquitously in eukaryotes. Autophagy is responsible for the degradation of most long-lived proteins and some organelles. Cytoplasmic constituents, including organelles, are sequestered into double-membrane autophagosomes, which subsequently fuse with lysosomes where their contents are degraded. This system has been implicated in various physiological processes including protein and organelle turnover, stress response, cellular differentiation, programmed cell death and pathological conditions. Defects in the autophagy machinery might have several consequences, as they have been associated with neurodegenerative disease and different forms of cancer. Thus, autophagy occupies a crucial position within the cell's metabolism, and its modulation may represent an alternative therapeutic strategy in several pathological settings including stroke, Alzheimer's, Huntington's, Parkinson's diseases and cancer. Recently, research has begun to identify some characteristics of neuronal autophagy. The results suggest that autophagy may provide a neuroprotective mechanism. However, there is evidence showing that dysfunction of autophagy in certain pathological situations can trigger and mediate programmed cell death. Autophagy has also been defined as prime suspect cause of non-apoptotic cellular demise. However, there is now mounting evidence that autophagy and apoptosis share several common regulatory elements that are crucial in any attempt to understand the dual role of autophagy in cell death and cell survival. It will be of fundamental importance to dissect whether autophagy is primarily a strategy for survival or whether autophagy can also be a part of a cell death programme and thus contribute to cell death. Many questions are open. Is autophagy a direct death execution pathway? Is autophagy an innocent bystander? Is autophagy a defence mechanism or just a scavenger or self-clearance tool in the cell? A profound understanding of the biological effects and the mechanisms underlying autophagy in neurones might be helpful in seeking effective new treatments for neurodegenerative diseases. Here, we review the defining characteristics of autophagy with special attention to its role in neurodegenerative disorders, and recent efforts to delineate the pathway of autophagic protein degradation in neurone.